Preparation of active ingredient dispersions and apparatus therefor

ABSTRACT

The invention relates to a process and an apparatus for preparing active ingredient dispersions, wherein an active ingredient is dissolved in a fluid gas, the fluid gas loaded with active ingredient is essentially completely dissolved in a liquid and is decompressed, and the gas is separated from the liquid loaded with active ingredient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a Divisional application of application Ser. No. 08/944,984, nowU.S. Pat. No. 6,197,836, which was filed on Oct. 07, 1997, as aContinuation application of application Ser. No. 08/544,450, filed Nov.17, 1995 now abandoned.

The present invention relates to a process and an apparatus forpreparing active ingredient dispersions.

BACKGROUND OF THE INVENTION

It is nowadays necessary in many sectors of the chemical industry toprepare active ingredient dispersions, eg. in the color and dye industryand the drugs industry. In this connection it is often impossible todisperse. the active ingredient, eg. the dye or the drug, directly in anaqueous liquid. In particular, the active ingredient particles are thennot in the desired micronized form.

The preparation of very finely divided, micronized carotenoids in anaqueous dispersion is described in DE-A 29 43 267. In this case, acarotenoid is dissolved in a supercritical gas in an autoclave, and theresulting solution is dispersed in a suitable aqueous colloidal matrix,which is located in a second autoclave, using an agitator. The resultingdispersion consists of droplets of fluid gas containing activeingredient in water. This two-phase system is decompressed, with the gasbeing continuously discharged from the autoclave, whereas the liquid canbe removed only batchwise after completion of the process. This processresults in an average particle size of the carotenoid of less than 1micron. A disadvantage is that phase separation may occur during thedecompression process so that the active ingredient is insufficientlystabilized by the liquid matrix. In addition, a loss of activeingredient must be accepted.

European Patent 0 322 687 proposes a process for preparing a drug formcomprising an active ingredient and a carrier. This entails a fluid gas,an active ingredient and carrier materials, which can also be dissolvedin a liquid, being introduced into a spray tower so that the fluid gaspicks up active ingredient and carrier. The fluid gas is subsequentlyseparated from the resulting active ingredient/carrier combination in aseparator so that the combination can be removed from the separator.This process produces dry active ingredient particles but not liquiddispersions. Fluid gas means a substance which is in the form of a gasor vapor under atmospheric pressure and which has been compressed to thevicinity of its critical point or beyond and is therefore in the form ofa sub- or supercritical fluid.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a process and anapparatus for preparing active ingredient dispersions which lead to aparticularly fine dispersion of the active ingredient in the dispersion.In particular, the micronized active ingredients must not agglomerate.

We have found that this object is achieved by the process describedherein. This entails an active ingredient being dissolved in a fluidgas, and the fluid gas loaded with active ingredient being finelydispersed in a liquid and, during this, essentially completelydissolved. The solid is formed during the dissolving process of thefluid gas. Each of the individual, finely distributed gas bubblescontains only little solid, so that the solid particles produced thereinare very small. Since the particles pass directly into the liquid, wherethey are preferably bound into protective colloids, and previously onlylittle solid is contained in each of the individual, finely distributedgas bubbles, agglomeration can be virtually ruled out. The solution isthen decompressed, and the gas is thus separated from the liquid loadedwith active ingredient. Part of the removed liquid loaded with activeingredient is preferably reused as dissolving liquid for the fluid gas.It is possible in this way to achieve a high concentration of themicro-particles in the dispersion, irrespective of the solubility of theactive ingredient in the fluid gas. Another preferred process is one inwhich the solution is not on decompression completely decompressed toatmospheric pressure so that the reused liquid loaded with activeingredient is preloaded with the fluid gas. It is possible in this wayto influence both the rate of formation of the solid particles and themorphology thereof. Furthermore, the complete dissolving of the gas inthe liquid ensures that the active ingredient passes completely from thegas into the liquid. The process can be carried out continuously orbatchwise, and in both cases there is no, or only negligible,agglomeration of particles, preferably because of the stabilization byprotective colloids.

The object is also achieved by a process in which an active ingredientis dissolved in a fluid gas, and the fluid gas loaded with activeingredient is dispersed in a liquid saturated with this gas, so that afirst dispersion of liquid and fluid gas loaded with active ingredientis formed. The active ingredient is in this case transferred to thephase boundary by molecular diffusion from the gas. The solid then formsonly at the phase boundary and passes from there directly into theliquid, where it is immediately stabilized, preferably by protectivecolloids, so that agglomeration is ruled out. This first dispersion ispassed through a holdup section to form a second dispersion of liquidloaded with active ingredient and fluid gas. The second dispersion isthen separated, without previous decompression, by phase separation intoa gas phase and a third dispersion of liquid and active ingredient. Partof the third dispersion is finally reused to form the first dispersionwith the fluid gas. It is advantageous that a large part of the gas canbe reused for dissolving the active ingredient without renewedcompression.

In another embodiment, an active ingredient is dissolved in a fluid gas,and the fluid gas loaded with active ingredient is decompressed to forma first dispersion of gas and active ingredient. This first dispersionis dispersed in a liquid to give a second dispersion which is passedthrough a holdup section and separated into a gas phase and a thirddispersion of liquid and active ingredient. Preferably part of the thirddispersion which has been separated off is reused as liquid to form thesecond dispersion.

It is preferred to recycle the gas which has been separated off and isreused as fluid gas for dissolving the active ingredient. The activeingredient used preferably consists of a mixture of a plurality ofactive ingredients. Preferred active ingredients are dyes, vitamins,carotenoids, polymers, liposomes, drugs or crop protection agents.Preferred fluid gases are CO₂, N₂O, ethylene, propane, H₂O, NH₃,hydro-carbons, alcohols and mixtures of these substances The preferredliquid used is water or an organic solvent which is preferablysupplemented with additions of protective colloids such as surfactants,polymers, celluloses, dextrins or proteins such as gelatin and/oremulsifiers or the like.

The object of the invention is also achieved by the apparatus describedherein. An apparatus according to the apparatus claims comprises anextractor for dissolving an active ingredient in a fluid gas, which isconnected via a line to a mixer for dissolving the fluid gas loaded withactive ingredient in a liquid. The liquid is fed to the mixer throughanother line. The apparatus additionally contains a holdup section whichis connected to a separator in which the gas is separated from theliquid containing active ingredient. The separator has discharge linesfor the gas which has been separated off and for the liquid which hasbeen separated off. The apparatus additionally contains a return feedfor part of the liquid which has been separated off to the mixer.

A decompression valve is preferably fitted between the holdup sectionand the separator. In a preferred embodiment, the discharge line for thegas which has been separated off returns the latter from the separatorto the extractor.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is described hereinafter by means of FIGS. 1 to 4. Inthese:

FIG. 1 shows experimental design for a first variant of the process,

FIG. 2 shows experimental design for a second variant of the process,

FIG. 3 shows experimental design for a third variant of the process,

FIG. 4 shows experimental design for a fourth variant of the process.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In FIG. 1, a gas 1 is converted with the aid of a compressor 2 into thesupercritical, ie. fluid, state. This fluid gas 3 takes up the activeingredient 5 in an extractor 4. The fluid gas loaded with activeingredient is then fed through line 6 to the mixer 7 where it is mixedwith a liquid which is fed through line 12 to the mixer. The fluid gasloaded with active ingredient is essentially completely dissolved in theliquid in the mixer 7 and the subsequent holdup section 8. The activeingredient dissolved in the fluid gas precipitates in the form of veryfinely dispersed particles with sizes in the range below 1 μm into theliquid. The resulting active ingredient/liquid dispersion isdecompressed through valve 9 and fed through line 10 to the separator11. Part of the liquid loaded with active ingredient is dischargedthrough line 15, and the other part is passed through line 16 andcompressor 13 together with fresh liquid, which is supplied by line 18,through line 12 to the mixer 7. This partial recycling makes it possibleto determine the concentration of active ingredient particles in thedispersion, irrespective of the solubility of active ingredient in thefluid gas. The gas which has been separated off is discharged throughline 14 and returned to the circulation upstream of the compressor 2.The solution can be completely decompressed, or else decompressed to apressure above atmospheric pressure, at the end of the holdup section.

An incomplete decompression, as depicted in FIG. 2, results in theliquid being preloaded with fluid gas, by which means it is possible toinfluence the crystallization rate in the formation of the activeingredient particles, just like their morphology. The recycling of thegas takes place in this case by the gas which has been separated offbeing discharged through line 14, compressed to the pressure of thesystem in the decompressor 17 and returned to the circulation throughline 20 downstream of the compressor 2. Fresh liquid is compressed inthe compressor 19 and fed to the circulation through line 18.

In the variant of the process which is depicted in FIG. 3, the fluid gasis likewise fed to the extractor 4 with the active ingredient 5 andreaches, as fluid gas loaded with active ingredient, the mixer 7.However, the fluid gas does not dissolve in the liquid in the mixer andthe subsequent holdup section 8, on the contrary the fluid gas loadedwith active ingredient is dispersed with a liquid, which is suppliedthrough line 12 and which is saturated with the same gas. The activeingredient dissolved in the fluid gas diffuses to the phase boundary,precipitates there in the form of micro- particles and is then bound inthe liquid, preferably by protective colloids. The second dispersion,which is now produced, of liquid loaded with active ingredient and offluid gas is not decompressed but is directly fed to a separator 11.Part of the liquid loaded with active ingredient is removed throughdischarge line 15, which is provided with a decompression valve 21. Thissolution is separated from dissolved gas in the separator 22 anddischarged through line 23. The gas is returned again via line 24upstream of the compressor 2. The other part of the liquid loaded withactive ingredient is discharged through line 16 out of the separator,supplemented with fresh liquid through line 18 and compressor 19 andcirculated by the circulating pump 13, which compensates the pressuredrop in the lines. The liquid is then fed through line 12 to the mixer 7again. The fluid gas which has been separated off is returned throughline 14, circulating pump 17 and line 20 to the extractor 4.

In the variant of the process shown in FIG. 4, the fluid gas loaded withactive ingredient is mixed in the mixer 7 with a liquid supplied throughline 12 and, at the same time, decompressed. The fluid gas containingactive ingredient is thus present in the form of gas bubbles in theliquid. The active ingredient particles diffuse at the phase boundary ofthe gas bubbles into the liquid. The resulting dispersion is thenseparated in the separator 11 into a gas phase and a third dispersion ofliquid and active ingredient. The liquid loaded with active ingredientis in turn discharged through discharge lines 15 and 16 or compressed inthe compressor and returned to the mixer. The gas which has beenseparated off is returned upstream of the compressor 2 for reuse asfluid gas.

EXAMPLE 1

About 5 g of β-carotene were introduced into a temperature-controllableautoclave with a capacity of 250 ml. An N₂O stream (250 bar-0.8 kg perhour) was preheated to 45° C. and passed into the autoclave. The N₂Ostream loaded with carotene was then fed through a thermostated line toa mixing nozzle. The gas stream was there dispersed in an aqueoussolution which contained 3.8% by weight of gelatin. During this thetemperature was 45° C. and the pressure was 250 bar. The dispersionsubsequently passed through a holdup section where the gas completelydissolved in the aqueous solution. Finally, the dispersion wasdecompressed in a separator, and the desorbed gas was separated from thesolution. The liquid was subsequently compressed again to 250 bar andreturned to the mixing nozzle. The particle size of the carotenecontained in the final product was distinctly below 1 μm.

EXAMPLE 2

As in Example 1, about 5 g of β-carotene were introduced into anautoclave. An N₂O stream (45° C., 250 bar, 0.8 kg per hour) was passedthrough the autoclave; the gas load dispersed as in Example 1 in anaqueous solution which contained 3.8% by weight of gelatin. Nodecompression took place. After intimate mixing of the compressed gaswith the aqueous solution in the holdup section, the compressed gas wasseparated off in a phase separator. The aqueous solution was conveyedback to the mixing nozzle. Since no decompression took place, thecirculated liquid was always saturated with N₂O, so that the compressedgas was unable to dissolve in the aqueous solution. Samples of theaqueous solution taken from the circulation and thereby decompressedconsisted of a dispersion of carotene particles which particle size wasdistinctly below 1 μm.

EXAMPLE 3

An N₂O stream loaded with β-carotene was produced as in the precedingexamples. This was decompressed through a mixing nozzle into an aqueoussolution which was conveyed under atmospheric pressure at 700 1 per hourand contained 3.8% by weight of gelatin. The resulting dispersion wassubsequently separated in a separator into a gas phase and a liquidloaded with active ingredient. The liquid phase, which assumed ayellow-orange color, was returned to the mixing nozzle. The particlesize of the carotene dispersed therein was once again below 1 μm.

We claim:
 1. A process for preparing an active ingredient dispersionwhich comprises: i) dissolving an active ingredient in a supercriticalfluid gas to form a supercritical fluid gas solution of the activeingredient, ii) dispersing the supercritical fluid gas solution of theactive ingredient in a gas-saturated liquid to form a first dispersionof the liquid and the supercritical fluid gas solution, wherein the gassaturating the liquid is the same as the gas utilized in supercriticalfluid form for dissolving the active ingredient, iii) passing the firstdispersion through a holdup section to form a second dispersion of theliquid comprising the active ingredient and the supercritical fluid gas,iv) separating the second dispersion without previous decompression intothe gas phase and a third dispersion of the liquid and the activeingredient, and v) recycling a part of the third dispersion to step(ii).
 2. The process of claim 1, wherein the gas phase formed in step(iv) is condensed and recycled into step (i) as the supercritical fluidgas.
 3. The process of claim 1, wherein the active ingredient consistsof a mixture of a plurality of active ingredients.
 4. The process ofclaim 3, wherein the plurality of active ingredients is selected fromthe group consisting of dyes, vitamins, carotenoids, polymers,liposomes, drugs, crop protection agents, proteins and peptides.
 5. Theprocess of claim 1, wherein the active ingredient is selected from thegroup consisting of dyes, vitamins, carotenoids, polymers, liposomes,drugs, crop protection agents, proteins and peptides.
 6. The process ofclaim 1, wherein the supercritical fluid gas is selected from the groupconsisting of fluid CO₂, N₂O, ethylene, propane, H₂O, NH₃, hydrocarbons,alcohols and mixtures thereof.
 7. The process of claim 1, wherein theliquid is water or an organic solvent, optionally in mixture withsurfactants, polymers, celluloses, dextrins, proteins and/oremulsifiers.
 8. The process of claim 7, wherein the liquid is water oran organic solvent in mixture with gelatin and optionally further withother proteins, surfactants, polymers, celluloses, dextrins and/oremulsifiers.